Dextroamphetamine

Dextroamphetamine is commercially available as dextroamphetamine, dextroamphetamine sulfate, and in mixed salt preparations containing either amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate or amphetamine, amphetamine aspartate, and dextroamphetamine sulfate.1, 2, 3, 4, 5, 101, 102, 103

Attention Deficit Hyperactivity Disorder

Dextroamphetamine sulfate conventional tablets (e.g., Zenzedi^®) and dextroamphetamine sulfate oral solution (e.g., ProCentra^®) are used for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients 3-16 years of age.1, 2 Dextroamphetamine sulfate sustained-release capsules (e.g., Dexedrine^® Spansule^®) are used for the treatment of ADHD in pediatric patients 6-16 years of age.102 Dextroamphetamine transdermal system (e.g., Xelstrym^®), amphetamine mixed salt biphasic extended-release capsules containing amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate (e.g., Adderall XR^®), and extended-release oral suspension and extended-release tablets containing amphetamine, amphetamine aspartate, and dextroamphetamine sulfate (e.g., Dyanavel^® XR), are used for the treatment of ADHD in adults and pediatric patients 6 years of age and older.3, 5, 103 Amphetamine mixed salt immediate-release conventional tablets containing amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate (e.g., Adderall^®) are used for the treatment of ADHD in pediatric patients 3 years of age and older.101 Amphetamine mixed salt triphasic extended-release capsules containing amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate (e.g., Mydayis^®) are used for the treatment of ADHD in adults and pediatric patients 13 years of age and older.4

Clinical Experience

Pediatric Patients

The safety and efficacy of dextroamphetamine transdermal system (e.g., Xelstrym^®) for the treatment of ADHD in pediatric patients were established in a multicenter, randomized, double-blind, placebo-controlled crossover laboratory classroom study in 110 pediatric patients 6-17 years of age.3, 104 After an initial 5 week open-label dose optimization period, pediatric patients with ADHD (inattentive, hyperactive/impulsive, or combined type) were randomized to receive either transdermal dextroamphetamine for 1 week followed by placebo for 1 week or placebo for 1 week followed by transdermal dextroamphetamine for 1 week during the 2-week double-blind treatment period.3, 104 At the start of the 5-week open-label period, patients applied a 5 mg dextroamphetamine transdermal system daily to their hip (alternating sides) for 9 hours.104 Doses were titrated at weekly visits to the next dose level (e.g., by 5 mg increments) based on the efficacy and tolerability until an optimal dose was achieved.104 The main efficacy measure assessed was the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) total score.104 The SKAMP scale is a validated subjective laboratory classroom scale that contains 13 items to assess manifestations of ADHD in a classroom setting.3 The mean age of patients in this study was 10.5 years; 69.1% were male.104 Transdermal dextroamphetamine, compared to placebo, was found to substantially improve SKAMP total scores over a 12-hour assessment period.104 The onset of effect was seen as soon as 2 hours after application of the transdermal system and extended through 12 hours post-application (transdermal system removed at 9 hours).104

In 2016, a Cochrane review of 23 trials enrolling 2675 patients compared the efficacy of amphetamines (any oral form including amphetamine, dextroamphetamine, lisdexamfetamine, and mixed amphetamine salts, at any dosage) to placebo for the treatment of ADHD in children and adolescents 3-17 years of age.109 Within this meta-analysis, there were 12 studies that assessed mixed amphetamine salts and 7 that assessed dextroamphetamine.109 The main efficacy outcome was change in core ADHD symptoms (i.e., inattention, hyperactivity, impulsivity).109 The Cochrane review found that amphetamines (any type) improved parent-rated, teacher-rated, clinician-rated, and investigator-rated ADHD symptoms.109

Adults

In 2018, a Cochrane review of 19 trials enrolling 2521 patients compared the efficacy of amphetamines (dextroamphetamine, lisdexamfetamine, and mixed amphetamine salts) with placebo for the treatment of ADHD in adults.111 Within this meta-analysis, there were 8 studies that assessed mixed amphetamine salts and 3 that assessed dextroamphetamine.111 The main efficacy outcome was the severity of ADHD symptoms assessed by clinicians and patients.111 The mean age of patients in this meta-analysis was 35.3 years of a 57.2% were male and 78.8% had a combined type of ADHD.111 This Cochrane review found evidence that suggests amphetamines are more efficacious than placebo in the reduction of the severity of clinician- and patient-assessed ADHD symptoms.111

Clinical Perspective

The American Academy of Pediatrics (AAP) has developed guidelines for children and adolescents with ADHD.112 For pediatric patients 6-12 years of age with ADHD, the provider should prescribe FDA-approved medications for ADHD, in addition to parent training in behavior management (PTBM) and/or behavioral classroom interventions.112 For the choice of medication, evidence is stated as particularly strong for stimulant medications (e.g., amphetamines, methylphenidate).112 Evidence is stated as sufficient but not as strong for atomoxetine, extended-release guanfacine, and extended-release clonidine.112 For adolescents 12-18 years of age with ADHD, the provider should prescribe FDA-approved medications with the assent of the adolescent.112 The provider is also encouraged to prescribe behavioral and other evidence-based training interventions if available.112 Doses of medications should be titrated to achieve maximum benefit with tolerable side effects.112

The AAP also provides recommendations for pediatric patients with ADHD as young as 4 years of age.112 The first lines of treatment for pediatric patients 4-6 years of age are PTBM and behavioral classroom interventions.112 The AAP states that methylphenidate may be considered if these behavioral interventions do not provide significant improvement and there is moderate to severe continued disturbance in the child's functioning; however, use of methylphenidate in this age group is considered off-label.112

International experts have published recommendations for the treatment of ADHD in adults.113, 114 Treatment of ADHD in adults should follow a multimodal approach that includes psychoeducation, pharmacotherapy, cognitive behavior therapy, and coaching for ADHD.113 First-line pharmacotherapy agents include long-acting stimulants such as mixed amphetamine salts, methylphenidate, and lisdexamfetamine.114 Short-acting and intermediate-acting stimulants (including dextroamphetamine) are considered second-line and can also be adjunctive agents.114 Atomoxetine may also be used as a second-line or adjunctive agent.114

Narcolepsy

Dextroamphetamine sulfate conventional tablets (e.g., Zenzedi^®), dextroamphetamine sulfate oral solution (e.g., ProCentra^®), dextroamphetamine sulfate sustained-release capsules (e.g., Dexedrine^® Spansule^®), and amphetamine mixed salt immediate-release conventional tablets containing amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate (e.g., Adderall^®) are also used in the treatment of narcolepsy in adults and pediatric patients 6 years of age and older.1, 2, 101, 102

Guidelines from the American Academy of Sleep Medicine (AASM) provide a strong recommendation for the use of several agents for the treatment of narcolepsy in adults including modafinil, pitolisant, sodium oxybate, and solriamfetol.115 A conditional recommendation is given for armodafinil, dextroamphetamine, and methylphenidate.115 These recommendations are derived from a systematic review and meta-analysis conducted by the AASM to assess the efficacy of interventions for the treatment of central disorders of hypersomnolence, including narcolepsy.116 The conditional recommendation of the use of dextroamphetamine for the treatment of narcolepsy is based on 1 randomized, double-blind, placebo-controlled trial in 12 patients, 1 observational single-blind study in 20 patients, and 1 retrospective observational case series in 60 patients.116 While the quality of evidence is rated as very low, the AASM analysis concluded that the balance between the desirable and undesirable effects was likely in favor of dextroamphetamine.116

Autism Spectrum Disorder

Dextroamphetamine and mixed amphetamine salts have been used for the symptomatic treatment of inattention, impulsivity, and hyperactivity in pediatric patients with autism spectrum disorder (ASD)†.117

The AAP has developed guidelines for children and adolescents with ASD.117 While there are not currently any medications that correct core social and communication symptoms in patients with ASD, there are medications that may be used to help manage behavioral and psychiatric symptoms.117 For symptoms of hyperactivity, impulsivity, inattention, and distractibility, the AAP suggests the use of psychostimulants (e.g., methylphenidate, dexmethylphenidate, mixed amphetamine salts, lisdexamfetamine, dextroamphetamine) after behavioral approaches are implemented if problems persist.117

Dosage and Administration ⬆ ⬇

General

Pretreatment Screening

Perform a thorough medical history review (including evaluation for a family history of sudden death or ventricular arrhythmia) and physical examination to detect the presence of cardiac disease prior to initiating stimulant therapy.1, 2, 3, 4, 5, 101, 102, 103
Prior to initiating stimulant therapy in patients with ADHD, obtain a detailed psychiatric history (e.g., current or prior depressive symptoms; family history of suicide, bipolar disorder, or depression) to determine if they are at risk for developing a manic episode.1, 2, 3, 4, 5, 101, 102, 103
Prior to initiation of therapy, assess for family history of motor or verbal tics or Tourette's syndrome, and clinically evaluate patients for such disorders.1, 2, 3, 4, 5, 101, 102, 103
Evaluate patients for risk of abuse, misuse, and addiction prior to initiating therapy.1, 2, 3, 4, 5, 101, 102, 103

Patient Monitoring

Routinely monitor for emergence or worsening of tics or Tourette's syndrome.1, 2, 3, 4, 5, 101, 102, 103
Closely monitor growth (weight and height) in pediatric patients receiving stimulant therapy.1, 2, 3, 4, 5, 101, 102, 103
Throughout treatment, reassess each patient's risk of abuse, misuse, and addiction.1, 2, 3, 4, 5, 101, 102, 103 Frequently monitor for signs of abuse, misuse, and addiction during treatment.1, 2, 3, 4, 5, 101, 102, 103
Monitor for hypertension and tachycardia.1, 2, 3, 4, 5, 101, 102, 103

Dispensing and Administration Precautions

The Institute for Safe Medication Practices (ISMP) includes Adderall^® and Adderall^® XR on their List of Confused Drug Names, and recommends using special safeguards to ensure the accuracy of prescriptions for these drugs.555
The manufacturer states that medication errors, including substitution and dispensing errors, can occur with Mydayis^® and other amphetamine products, which can lead to potential overdosage.4 To avoid potential errors and overdosage, Mydayis^® should not be substituted with other amphetamine products on a milligram-per-milligram basis due to different amphetamine base compositions and differences in pharmacokinetics.4

Administration

Preparations containing dextroamphetamine sulfate are administered orally or transdermally.1, 2, 3, 4, 5, 101, 102, 103

The following dextroamphetamine formulations are commercially available in the US: immediate-release dextroamphetamine sulfate conventional tablets (e.g., Zenzedi^®); immediate-release dextroamphetamine sulfate oral solution (e.g, ProCentra^®); dextroamphetamine sulfate sustained-release capsules (e.g., Dexedrine^® Spansule^®); dextroamphetamine transdermal system (e.g., Xelstrym^®); immediate-release conventional tablets containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Adderall^®); triphasic extended-release capsules containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Mydayis^®); biphasic extended-release capsules containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Adderall XR^®); extended-release tablets containing amphetamine, amphetamine aspartate, and dextroamphetamine sulfate (e.g., Dyanavel^® XR); and extended-release oral suspension containing amphetamine, amphetamine aspartate, and dextroamphetamine sulfate (e.g., Dyanavel^® XR).1, 2, 3, 4, 5, 101, 102, 103

Oral Administration

Immediate-release Tablets and Oral Solution

The initial dose of dextroamphetamine sulfate (alone or in fixed-combination preparations) is given on awakening; when the medication is given in 2 or 3 divided doses, additional doses are given at intervals of 4-6 hours.1, 2, 101 Because of the potential for insomnia, administration of immediate-release preparations should be avoided in the late evening.1, 2, 101

Store at 20-25°C in a tight, light-resistant container;1, 2, 101 excursions are permitted between 15-30°C for immediate-release dextroamphetamine sulfate tablets (e.g., Zenzedi^®).1

Sustained-release Capsules

The commercially available sustained-release capsules containing dextroamphetamine sulfate (Dexedrine^® Spansule^®) may be taken with or without food.102 Store at 20-25°C in a tight, light-resistant container.102

Extended-release Capsules

The commercially available extended-release capsules containing dextroamphetamine sulfate and dextroamphetamine saccharate in fixed combination with amphetamine sulfate and amphetamine aspartate monohydrate (Adderall XR^®; Mydayis^®) may be swallowed intact with or without food; alternatively, the entire contents of the capsule may be sprinkled on a small amount of applesauce immediately prior to administration.4, 103 Subdividing the contents of a capsule is not recommended.4, 103 The manufacturer states that Mydayis^® should be administered in a consistent manner relative to food intake.4 The pellets contained in the capsules should not be chewed or crushed, and the sprinkle/food mixture must not be stored for use at a later time.103

The daily dose of amphetamines (as extended-release capsules) should be given on awakening.4, 103 Administration of extended-release capsules in the afternoon should be avoided because of the potential for insomnia.4 In the event of a missed dose, doses should not be administered later in the day.4, 103

Store at 20-25°C; excursions are permitted between 15-30°C.4, 103

Extended-release Tablets

Extended-release tablets containing amphetamine, amphetamine aspartate, and dextroamphetamine sulfate (Dyanavel^® XR) are administered once daily in the morning without regard to meals.5

The tablets may be chewed or swallowed whole.5 Dosing increments of 2.5 mg can be attained by dividing the functionally scored 5 mg extended-release tablet into equal halves at the score line.5

Store at 20-25°C; excursions are permitted between 15-30°C.5

Extended-release Oral Suspension

Extended-release oral suspension containing amphetamine, amphetamine aspartate, and dextroamphetamine sulfate (Dyanavel^® XR) is administered once daily in the morning without regard to meals.5

The bottle adapter should be firmly inserted into the bottle prior to use and not removed after insertion.5 The bottle of suspension should be shaken well before each administration.5 The oral dosing dispenser supplied by the pharmacist should be used to administer the oral suspension.5

Store at 20-25°C; excursions are permitted between 15-30°C.5

Transdermal Administration

Patients receiving transdermal dextroamphetamine (Xelstrym^®) should be carefully instructed in the proper use and disposal of the transdermal system.3

The dextroamphetamine transdermal system should be applied once daily in the morning, 2 hours before an effect is needed, and should be removed 9 hours after application.3 Only one transdermal system should be used per 24-hour period.3 The system should be applied immediately after opening the pouch and removing the slip from above and below the patch; the system should not be used if the patch is cut or damaged.3 While avoiding touching the adhesive side, half of the clear plastic liner should be peeled away from the middle of the patch, applied to the application site, and smoothed down.3 While holding the edge of the remaining protective liner, slowly peel the rest of the liner off, smooth the rest of the patch down, and press the patch with the palm of the hand to make sure it sticks well.3 After applying the system or if the adhesive side is touched, the hands should be washed immediately with soap and water.3 The adhesive side of the transdermal system should be placed on clean (void of lotions, oils, or gels), intact, dry areas of the hip, upper arm, chest, upper back, or flank; application of the transdermal system to the waistband or straps should be avoided.3 Application sites should be alternated daily.3

The patch should be checked regularly to ensure adhesion to the application site. It should also be checked after using the bathroom, sleeping, bathing, swimming, showering, undressing or changing clothes, or if sweating a lot.3 If the edges of the patch lift, the patch may be pressed firmly and smoothed down; dressings, tape, or other common adhesives should not be used to ensure adhesion.3 If a system falls off during the intended period of use, it should be replaced with a new system applied at a different site, but the total wear time should not exceed 9 hours per day regardless of the number of transdermal systems used for replacement.3

The transdermal system should be removed by peeling it off the skin.3 If any adhesive remains on the skin after the transdermal system has been removed, an oil-based product or water and soap may be applied to the application site to gently loosen and remove any residual adhesive.3 Hand washing with soap and water is recommended after the patch has been removed.3

After removal, used systems should be folded in half so that the adhesive side adheres to itself and then disposed of in an appropriate lidded container.3 Any unused systems that are no longer needed should be removed from their packaging, separated from the protective liner, folded so that the adhesive side adheres to itself, and then disposed of in an appropriate lidded container.3

Dextroamphetamine transdermal systems should be stored at 20-25°C protected from light, but may be exposed to temperatures ranging from 15-30°C; they should be kept sealed in the original pouch until use.3

Dosage

Dosage of dextroamphetamine sulfate for the treatment of attention deficit hyperactivity disorder (ADHD) should be individualized based on patient response and tolerance.101, 102, 103 The smallest dose required to produce the desired response should always be used.1, 2, 102

The manufacturer states that the total daily dosage of immediate-release mixed amphetamine salts (Adderall^®) is bioequivalent to the same total daily dosage of mixed amphetamine salts extended-release capsules (Adderall XR^®) administered once daily.103

Manufacturers state that Mydayis^® should not be substituted with other amphetamine products on a milligram-per-milligram basis due to different amphetamine base compositions and pharmacokinetic profiles.4

Substitution of Dyanavel^® XR extended-release oral suspension for Dyanavel^® XR extended-release oral tablets may occur on a milligram-per-milligram basis; however, other amphetamine products should not be substituted on a milligram-per-milligram basis due to different amphetamine base compositions and pharmacokinetic profiles.5

Dosages of Dyanavel^® XR are expressed as the amount of amphetamine base,5 and dosages of Xelstrym^® are expressed as the amount of dextroamphetamine delivered over 9 hours;3 the dosages of other dextroamphetamine products are expressed in terms of the total amount of the salt(s).1, 2, 4, 101, 102, 103

Adults

Attention Deficit Hyperactivity Disorder

Extended-release Capsules (Adderall XR®, Mydayis®)

In adults who are receiving drug therapy for ADHD for the first time or being switched from therapy with another medication, the recommended dosage of extended-release capsules containing mixed amphetamine salts (Adderall XR^®) is 20 mg once daily.103 When switching from conventional tablets to extended-release capsules, the total daily dosage of amphetamines may remain the same but should be given once daily.103 Although dosages of up to 60 mg daily (as extended-release capsules) have been used in adults in clinical studies, there is no evidence that dosages exceeding 20 mg daily provide any additional benefit in these patients.103

In adults who are receiving drug therapy for ADHD for the first time or are being switched from therapy with another stimulant, therapy may be initiated with extended-release capsules containing mixed amphetamine salts (Mydayis^®).4 In adults, the initial dosage of extended-release capsules containing mixed amphetamine salts (Mydayis^®) is 12.5 mg once daily immediately upon awakening; an initial dose of 25 mg once daily may be considered for some patients.4 The daily dosage may be increased in increments of 12.5 mg no sooner than weekly based on clinical response to a maximum dosage of 50 mg once daily.4 Dosages >50 mg daily have not been shown to provide additional benefit in adults in clinical studies.4 Because the duration of action is estimated to last for up to 16 hours, the medication should be administered immediately upon awakening to reduce the potential for insomnia.4

Extended-release Tablets and Oral Suspension (Dyanavel® XR)

In patients who are receiving medication therapy for ADHD for the first time or are being switched from therapy with another stimulant, the initial dosage of extended-release amphetamine tablets and extended-release oral suspension is 2.5 or 5 mg once daily in the morning; the daily dosage may be increased by 2.5-10 mg at 4- to 7-day intervals until the optimum response is attained.5 The maximum recommended dosage is 20 mg once daily.5 The duration of action of Dyanavel^® XR is approximately 13 hours; the medication should be administered immediately upon awakening to reduce the potential for insomnia.4 .554

Transdermal System (Xelstrym®)

In adult patients who are receiving medication therapy for ADHD for the first time or are being switched from therapy with another stimulant, the recommended initial dosage of the dextroamphetamine transdermal system is 9 mg over a 9-hour period.3 The dosage may be individualized and titrated to a maximum of 18 mg over a 9-hour period based on clinical response and tolerability.3

Narcolepsy

In the treatment of narcolepsy, the usual dosage of dextroamphetamine sulfate given alone (Procentra^®, Zenzedi^®, Dexedrine^® Spansule^®) or the total dosage of amphetamines given in a fixed-combination preparation of amphetamine salts (Adderall^®) is 5-60 mg daily, depending upon the patient's age and response, usually given in divided doses.1, 2, 101, 102 In adults, the initial dosage is 10 mg daily; daily dosage is increased by 10 mg at weekly intervals until the optimum response is attained.1, 2, 101, 102 When intolerable adverse effects occur (e.g., insomnia, anorexia), dosage should be reduced.1, 2, 101, 102 Dextroamphetamine sulfate extended-release capsules may be used for once-daily dosing whenever appropriate.102

Pediatric Patients

Attention Deficit Hyperactivity Disorder

Immediate-release Oral Preparations (Adderall®, Procentra®, Zenzedi®)

As an adjunct in the treatment of ADHD in children 3-5 years of age, the initial daily dosage of dextroamphetamine sulfate given in conventional (short-acting) preparations as tablets or oral solution is 2.5 mg; daily dosage is increased by 2.5 mg at weekly intervals until the optimum response is attained.1, 2 In children ≥6 years of age, the initial dosage is 5 mg once or twice daily; daily dosage is increased by 5 mg at weekly intervals until the optimum response is attained.1, 2 Total daily dosage rarely should exceed 40 mg.1, 2 When the medication is administered as conventional tablets or oral solution in 2 or 3 divided doses, additional doses are given at intervals of 4-6 hours.1, 2

As an adjunct in the treatment of ADHD in children 3-5 years of age, the initial daily dosage of mixed amphetamine salts (Adderall^®) is 2.5 mg; daily dosage is increased by 2.5 mg at weekly intervals until the optimum response is attained.101 In children ≥6 years of age, the initial total dosage of amphetamines is 5 mg once or twice daily.101 The daily dosage is increased by 5 mg at weekly intervals until the optimum response is attained; total daily dosage rarely should exceed 40 mg.101 The manufacturer recommends that the initial dose of mixed amphetamine salts (Adderall^®) be given on awakening; additional doses (1 or 2) are given at intervals of 4-6 hours.101

Sustained-release Capsules (Dexedrine® Spansule®)

When dextroamphetamine sulfate sustained-release capsules (Dexedrine^® Spansule^®) are used for the treatment of ADHD in children ≥6 years of age, the initial dosage is 5 mg once or twice daily.102 The daily dosage may be increased by 5 mg at weekly intervals until the optimum response is attained; total daily dosage rarely should exceed 40 mg.102

Dextroamphetamine sulfate sustained-release capsules may be substituted for the conventional short-acting preparation if less frequent daily dosing is desired.102

Extended-release Capsules (Adderall XR®, Mydayis®)

In pediatric patients who are receiving medication therapy for ADHD for the first time or are being switched from therapy with another stimulant, dextroamphetamine therapy may be initiated with extended-release capsules containing mixed amphetamine salts (Adderall XR^®).103 In children 6-12 years of age, the initial dosage of extended-release capsules containing mixed amphetamine salts (Adderall XR^®) is 10 mg once daily; daily dosage may be increased in increments of 5 or 10 mg at weekly intervals to a maximum dosage of 30 mg daily.103 Treatment may be initiated with a dosage of 5 mg once daily when, in the opinion of the clinician, a lower initial dosage is appropriate.103

In adolescents 13-17 years of age, the initial dosage of extended-release capsules containing mixed amphetamine salts (Adderall XR^®) is 10 mg once daily.103 Dosage may be increased to 20 mg once daily after 1 week if symptoms are not adequately controlled.103 The duration of action of Adderall XR^® is approximately 10-12 hours.554 Although dosages of up to 60 mg daily (as extended-release capsules) have been used in adolescents 13-17 years of age in clinical studies, there is no evidence that dosages >20 mg daily provide any additional benefit in these patients.103

In adolescents 13-17 years of age who are receiving drug therapy for ADHD for the first time or are being switched from therapy with another stimulant, amphetamine therapy may be initiated with extended-release capsules containing mixed amphetamine salts (Mydayis^®).4 In adolescents 13-17 years of age, the initial dosage of extended-release capsules containing mixed amphetamine salts (Mydayis^®) is 12.5 mg once daily immediately upon awakening; daily dosage may be increased in increments of 12.5 mg no sooner than weekly based on clinical response to a maximum dosage of 25 mg once daily.4 Dosages >25 mg once daily have not been evaluated in pediatric patients in clinical studies.4 Because the duration of action of Mydayis^® is estimated to be up to 16 hours, the medication should be administered immediately upon awakening to reduce the potential for insomnia.4

Extended-release Tablets and Oral Suspension (Dyanavel® XR)

In children ≥6 years of age who are receiving drug therapy for ADHD for the first time or are being switched from therapy with another stimulant, the initial dosage of extended-release amphetamine tablets and extended-release oral suspension is 2.5 or 5 mg once daily in the morning; the daily dosage may be increased by 2.5-10 mg at 4- to 7- day intervals until the optimum response is attained.5 The maximum recommended dosage is 20 mg once daily.5 The duration of action of Dyanavel^® XR is approximately 13 hours; the medication should be administered immediately upon awakening to reduce the potential for insomnia.4 .554

Transdermal System (Xelstrym®)

For the treatment of ADHD in children ≥6 years of age who are receiving medication therapy for ADHD for the first time or are being switched from therapy with another stimulant, the recommended initial dosage of the dextroamphetamine transdermal system is 4.5 mg per 9-hour period; dosage may be increased in weekly increments of 4.5 mg to a maximum recommended dosage of 18 mg per 9-hour period based on clinical response and tolerability.3

Narcolepsy

In the treatment of narcolepsy, the usual dosage of dextroamphetamine sulfate given alone (Procentra^®, Zenzedi^®, Dexedrine^® Spansule^®) or the total dosage of amphetamines given in a fixed-combination preparation of amphetamine salts (Adderall^®) is 5-60 mg daily, depending upon the patient's age and response, usually given in divided doses.1, 2, 101, 102 In patients ≥12 years of age, the initial dosage is 10 mg daily; daily dosage is increased by 10 mg at weekly intervals until the optimum response is attained.1, 2, 101, 102 Although narcolepsy seldom occurs in children, in pediatric patients 6-12 years of age, the recommended initial dosage is 5 mg daily; daily dosage is increased by 5 mg at weekly intervals until the optimum response is attained.1, 2, 101, 102 Dextroamphetamine sulfate extended-release capsules may be used for once-daily dosing whenever appropriate.102

Special Populations

Hepatic Impairment

Manufacturers do not provide specific dosage recommendations, although the presence of hepatic impairment has the potential to reduce drug elimination and prolong exposure.1, 2, 3, 4, 5, 101, 102, 103

Renal Impairment

The presence of renal impairment has the potential to reduce drug elimination and prolong exposure.1, 2, 3, 4, 5, 101, 102, 103 Dextroamphetamine is not removed by dialysis.3

In patients with severe renal impairment, the maximum dose of Xelstrym^® should not exceed 13.5 mg per 9-hour period.3 In patients with end-stage renal disease (ESRD), the maximum dose of Xelstrym^® should not exceed 9 mg per 9-hour period.3

In adults with severe renal impairment (glomerular filtration rate [GFR] 15 to <30 mL/minute per 1.73 m²), the recommended initial dosage of fixed-combination preparation Mydayis^® is 12.5 mg once daily, which may be further increased to a maximum of 25 mg daily.4 In adolescents 13-17 years of age with severe renal impairment, the maximum recommended dosage of Mydayis^® is 12.5 mg daily if tolerated; the dosage should not be further escalated.4

The recommended initial dosage of Adderall XR^® in adults with severe renal impairment is 15 mg once daily in the morning.103 In children and adolescents 6-17 years of age with severe renal impairment, the recommended dosage of Adderall XR^® is 5 mg once daily.103 The maximum recommended dosage of Adderall XR^® in children 6-12 years of age with severe renal impairment is 20 mg once daily.103

Mydayis^® and Adderall XR^® are not recommended in patients with end-stage renal disease (ESRD; GFR <15 mL/minute per 1.73 m²).4, 103

Geriatric Patients

Dextroamphetamine has not been studied in the geriatric patient population.1, 2, 3, 4, 5, 101, 102, 103 Generally, dosage selection for geriatric patients should start at the lower end of the dosage range, reflecting the greater frequency of reduced hepatic, renal, or cardiac function and of concomitant diseases and medication therapy in geriatric patients.1, 2, 3, 4, 5, 101, 102, 103

Cautions ⬆ ⬇

Contraindications

Hypersensitivity to dextroamphetamine or other components of the formulation.1, 2, 3, 4, 5, 101, 102, 103
Concomitant use of monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing an MAOI (including linezolid and IV methylene blue), because of the increased risk of hypertensive crisis.1, 2, 3, 4, 5, 101, 102, 103

Warnings/Precautions

Warnings

Abuse, Misuse, and Addiction

A boxed warning is included in the prescribing information for dextroamphetamine concerning the high potential for abuse and misuse.1, 2, 3, 4, 5, 101, 102, 103 The use of dextroamphetamine exposes patients to the risks of abuse and misuse, which can lead to the development of substance use disorder (including addiction).1, 2, 3, 4, 5, 101, 102, 103 Misuse and abuse of CNS stimulants such as dextroamphetamine can result in overdose or death.1, 2, 3, 4, 5, 101, 102, 103 This risk is further increased with higher dosages or unapproved routes of administration (i.e., snorting, injection).1, 2, 3, 4, 5, 101, 102, 103 Because CNS stimulants, including dextroamphetamine, have a high potential for abuse and dependence, the risk of abuse, misuse, and addiction should be assessed prior to initiating dextroamphetamine and frequently for the duration of therapy.1, 2, 3, 4, 5, 101, 102, 103 Patients receiving stimulants should be also monitored for signs of abuse, misuse, and addiction.1, 2, 3, 4, 5, 101, 102, 103

In addition, tolerance can develop during dextroamphetamine therapy, which is characterized by a reduced response to the medication after repeated administration.1, 2, 3, 4, 5, 101, 102, 103 In patients who are physically dependent on CNS stimulants, abrupt cessation of therapy, rapid dosage reduction, or administration of an antagonist may result in a withdrawal syndrome characterized by dysphoric mood, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.1, 2, 3, 4, 5, 101, 102, 103

Patients and/or their caregivers should be advised that dextroamphetamine can be abused and can result in dependence; they should be advised that dextroamphetamine should not be shared with others and should be stored in a safe (preferably locked) location to prevent misuse and abuse.1, 2, 3, 4, 5, 101, 102, 103 Dextroamphetamine should be disposed of by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site when it is no longer needed.1, 2, 3, 4, 5, 101, 102, 103 If there is no take-back program or authorized DEA collection site available, the medication can be mixed with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds and disposed of in a sealed plastic bag in the household trash.1, 2, 3, 4, 5, 101, 102, 103 Unused patches should be removed from their individual pouch, separated from the protective liner, folded in half so the adhesive sides attach together, and disposed of in a container with a lid in the household trash.3 The patch, pouch, or liner should not be flushed down the toilet.3

Other Warnings/Precautions

Risks to Patients with Serious Cardiac Disease

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease receiving usual dosages of stimulants for the treatment of ADHD.1, 2, 3, 4, 5, 101, 102, 103

Children, adolescents, and adults who are being considered for stimulant therapy should undergo a thorough medical history review (including evaluation for a family history of sudden death or ventricular arrhythmia) and physical examination to detect the presence of cardiac disease.1, 2, 3, 4, 5, 101, 102, 103 In general, CNS stimulants should not be used in children, adolescents, or adults with known serious structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease.1, 2, 3, 4, 5, 101, 102, 103

Patients or caregivers should inform clinicians immediately if adverse cardiovascular effects (e.g., exertional chest pain, unexplained syncope, other symptoms suggestive of cardiac disease) occur during stimulant therapy.1, 2, 3, 4, 5, 101, 102, 103

Increased Blood Pressure and Heart Rate

Stimulants, including dextroamphetamine, can cause increases in average blood pressure by about 2-4 mm Hg and heart rate by about 3-6 beats/minute; larger increases may occur in some patients.1, 2, 3, 4, 5, 101, 102, 103 All patients should be monitored for hypertension and tachycardia.1, 2, 3, 4, 5, 101, 102, 103

Psychiatric Adverse Effects

Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, mania) have been reported in patients without a history of psychotic illness or mania who received usual dosages of stimulants.1, 2, 3, 4, 5, 101, 102, 103 In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% of patients receiving stimulants compared with 0% of those receiving placebo.1, 2, 3, 4, 5, 101, 102, 103 If psychotic or manic symptoms occur during stimulant therapy, discontinuance of therapy should be considered.1, 2, 3, 4, 5, 101, 102, 103

Stimulants have the potential to precipitate mixed or manic episodes in patients with comorbid bipolar disorder.1, 2, 3, 4, 5, 101, 102, 103 Prior to initiating stimulant therapy, patients with ADHD should be carefully screened to determine if they are at risk for developing a manic episode; such screening should include a detailed psychiatric history (e.g., current or prior depressive symptoms; family history of suicide, bipolar disorder, or depression).1, 2, 3, 4, 5, 101, 102, 103

Stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.1, 2, 3, 4, 5, 101, 102, 103

Long-term Suppression of Growth in Pediatric Patients

Therapy with CNS stimulants has been associated with weight loss and a slowing of growth in children.1, 2, 3, 4, 5, 101, 102, 103

Therefore, the manufacturers of stimulant preparations state that growth (weight and height) should be closely monitored during therapy with stimulants, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy.1, 2, 3, 4, 5, 101, 102, 103

Peripheral Vasculopathy, including Raynaud's Phenomenon

Because stimulants used to treat ADHD, including dextroamphetamine, are associated with peripheral vascular disorders, including Raynaud's phenomenon, careful observation for digital changes is warranted during stimulant therapy, and further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for certain patients who develop signs or symptoms of peripheral vasculopathy.1, 2, 3, 4, 5, 101, 102, 103

Seizures

Some evidence suggests that stimulants may lower the seizure threshold in patients with a history of seizures, in those with prior electroencephalography (EEG) abnormalities without seizures, and rarely, in patients without prior seizures or EEG abnormalities.1, 2, 3, 4, 5, 101, 102, 103 If seizures occur in a patient receiving dextroamphetamine, the drug should be discontinued.1, 2, 3, 4, 5, 101, 102, 103

Serotonin Syndrome

Potentially fatal serotonin syndrome can occur when dextroamphetamine is used in conjunction with other medications that affect serotonergic neurotransmitters, such as MAOIs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort ( Hypericum perforatum ).1, 2, 3, 4, 5, 101, 102, 103 Symptoms of serotonin syndrome can include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).1, 2, 3, 4, 5, 101, 102, 103 Amphetamines and amphetamine derivatives are metabolized to some extent by cytochrome P-450 (CYP) isoenzyme 2D6, and to a minor extent, inhibit CYP2D6 metabolism.1, 2, 3, 4, 5, 101, 102, 103 Therefore, there is a potential pharmacokinetic interaction when amphetamines are used concomitantly with CYP2D6 inhibitors.1, 2, 3, 4, 5, 101, 102, 103 In patients receiving concomitant CYP2D6 inhibitors, an alternative nonserotonergic medication, or medication that does not also inhibit CYP2D6 should be considered.1, 2, 3, 4, 5, 101, 102, 103

Concomitant use of amphetamines with other serotonergic medications or CYP2D6 inhibitors should only be considered if potential benefits justify the potential risks.4 If clinically feasible, consider initiating amphetamine therapy at a lower dosage and monitoring patients for the emergence of serotonin syndrome during therapy initiation or titration.1, 2, 3, 4, 5, 101, 102, 103 Patients should be informed of the risk of serotonin syndrome.1, 2, 3, 4, 5, 101, 102, 103 If symptoms of serotonin syndrome occur, amphetamines and any concomitant serotonergic agents should be immediately discontinued, and supportive care initiated.1, 2, 3, 4, 5, 101, 102, 103

Motor and Verbal Tics, and Worsening of Tourette's Syndrome

Onset or exacerbation of motor or verbal tics and worsening of Tourette's syndrome have been reported with CNS stimulants, including amphetamines.1, 2, 3, 4, 5, 101, 102, 103

Prior to initiation of therapy, patients should be screened for a family history and clinically evaluated for motor or verbal tics or Tourette's syndrome.1, 2, 3, 4, 5, 101, 102, 103 Patients receiving amphetamines should be routinely monitored for the emergence or worsening of tics or Tourette's syndrome, and treatment discontinued if clinically needed.1, 2, 3, 4, 5, 101, 102, 103

Contact Sensitization

Use of the dextroamphetamine transdermal system can lead to contact sensitization, also known as allergic contact dermatitis.3 Contact sensitization can be suspected if there is erythema with edema, papules, or vesicles that does not improve within 48 hours or spreads beyond the application site; erythema alone does not indicate contact sensitization.3 If contact sensitization is suspected, the transdermal system should be discontinued.3

In patients who develop contact sensitization to the dextroamphetamine transdermal system but require stimulant medications, oral amphetamine therapy should only be initiated under close medical supervision.3 Some patients who develop sensitization from the transdermal system may not be able to tolerate amphetamines in other formulations.3

Application Site Reactions

Local skin reactions (e.g., pain, pruritis, burning sensation, erythema, discomfort, edema, swelling) have been reported during wear time of the dextroamphetamine transdermal system and immediately following removal.3 Reactions during wear time usually resolved 2-4 hours following application of the transdermal system.3

In order to minimize skin irritation, discomfort, or pain, the application site should be changed each day.3

Use of External Heat

When heat is applied to the dextroamphetamine patch, the rate and extent of drug absorption are increased.3 Advise patients to avoid exposing the patch to direct heat sources such as hair dryers, heating pads, electric blankets, and heated water beds.3

Potential for Overdosage Due to Medication Errors

The manufacturer states that medication errors, including substitution and dispensing errors, can occur with Mydayis^® and other amphetamine products, which can lead to potential overdosage.4 To avoid potential errors and overdosage, Mydayis^® should not be substituted with other amphetamine products on a milligram-per-milligram basis due to different amphetamine base compositions and differences in pharmacokinetics.4

Specific Populations

Pregnancy

The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in females exposed to ADHD medication during pregnancy.1, 2, 3, 4, 5, 101, 103 Clinicians are encouraged to register females who become pregnant while receiving amphetamines by calling 1-866-961-2388 or visiting [Web].1, 2, 3, 4, 5, 101, 102, 103

Available data from published studies and postmarketing reports have not identified a drug-associated risk of major birth defects and miscarriage in females exposed to amphetamine during pregnancy.1, 2, 3, 4, 5, 101, 102, 103 Adverse pregnancy outcomes, including premature delivery and low birth weight, have been observed in infants of mothers taking amphetamines.1, 2, 3, 4, 5, 101, 102, 103

In embryofetal development studies in rats and rabbits, no effects on morphologic development were observed following oral administration of amphetamine during organogenesis.1, 2, 3, 4, 5, 101, 102, 103 In a pre- and postnatal development study in rats, oral administration of amphetamine throughout pregnancy and lactation was associated with decreased pup weight, which correlated with delayed development, and with decreased pup survival.1, 2, 3, 4, 5, 101, 102, 103 Adverse effects on pup reproductive performance were also observed.1, 2, 3, 4, 5, 101, 102, 103 Animal developmental studies have also reported long-term neurochemical and behavioral effects.1, 2, 3, 4, 5, 101, 102, 103

Amphetamines can cause vasoconstriction and may decrease placental perfusion.1, 2, 3, 4, 5, 101, 102, 103 Additionally, amphetamines can stimulate uterine contractions, increasing the risk of preterm delivery.1, 2, 3, 4, 5, 101, 102, 103 Infants born to mothers receiving amphetamines during pregnancy are an increased risk of preterm delivery and low birth weight.1, 2, 3, 4, 5, 101, 102, 103

Infants born to mothers receiving amphetamines during pregnancy should be monitored for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.1, 2, 3, 4, 5, 101, 102, 103

Lactation

Based on limited reports, amphetamine is present in human milk at a relative infant dose of 2-13.8% of the maternal weight-adjusted dosage and has a milk/plasma ratio between 1.9 and 7.5.1, 2, 3, 4, 5, 101, 102, 103 There have been no reports of adverse effects from amphetamine exposure on the breast-fed infant.1, 2, 3, 4, 5, 101, 102, 103 Long-term neurodevelopmental effects from amphetamine exposure through the breast milk are not known.1, 2, 3, 4, 5, 101, 102, 103 There is the potential that large doses of amphetamine could interfere with milk production, particularly in mothers whose lactation has not been established.1, 2, 3, 4, 5, 101, 102, 103 Because of the potential for serious adverse effects in breast-fed infants, breastfeeding is not recommended during amphetamine therapy.1, 2, 3, 4, 5, 101, 102, 103

Pediatric Use

Safety and efficacy of immediate-release dextroamphetamine tablets (Zenzedi^®), immediate-release dextroamphetamine oral solution (ProCentra^®), and immediate-release mixed amphetamine salts (Adderall^®) have been established for ADHD in pediatric patients ≥3 years of age.1, 2, 101 Safety and efficacy of these preparations have not been established in pediatric patients <3 years of age.1, 2, 101

Safety and efficacy of dextroamphetamine sustained-release capsules (Dexedrine^® Spansule^®) have been established for ADHD in pediatric patients ≥6 years of age.102 Use of the dextroamphetamine sustained-release capsule formulation is not recommended in children <6 years of age.102

Safety and efficacy of amphetamine extended-release oral tablets and suspension (Dyanavel^® XR) and the dextroamphetamine transdermal system (Xelstrym^®) are established for ADHD in pediatric patients 6-17 years of age.3, 5 Safety and efficacy of these preparations have not been established in children<6 years of age.3, 5

Safety and efficacy of extended-release capsules containing mixed amphetamine salts (Mydayis^®) have been established for ADHD in pediatric patients 13-17 years of age.4 Safety and efficacy of extended-release capsules containing mixed amphetamine salts have not been established for ADHD in pediatric patients ≤12 years of age.4 Although extended-release capsules containing mixed amphetamine salts have been studied in patients 6-12 years of age in 2 clinical studies, a safe and effective dosage has not been established in patients ≤12 years of age.4

Safety and efficacy of extended-release capsules containing mixed amphetamine salts (Adderall XR^®) have been established for ADHD in pediatric patients ≥6 years of age.103 Safety and efficacy of extended-release capsules containing mixed amphetamine salts have not been established for ADHD in pediatric patients <6 years of age.103

Long-term effects of amphetamines are not well established in the pediatric patient population.103

Geriatric Use

Clinical studies of amphetamine did not include a sufficient number of patients ≥65 years of age to assess differences in response compared to younger adults.1, 2, 3, 4, 5, 101, 102, 103 Other reported clinical experience has not identified differences in response between geriatric patients and younger adults.1, 2, 3, 4, 5, 101, 102, 103

Hepatic Impairment

Pharmacokinetic studies have not been conducted to evaluate the effects of hepatic impairment on amphetamine exposure.1, 2, 3, 4, 5, 101, 102, 103 Hepatic impairment has the potential to inhibit elimination and prolong exposure of amphetamines.1, 2, 3, 4, 5, 101, 102, 103

Renal Impairment

Pharmacokinetic studies have not been conducted to evaluate the effects of renal impairment on amphetamine exposure.1, 2, 3, 4, 5, 101, 102, 103 Renal impairment has the potential to inhibit elimination and prolong exposure of amphetamines.1, 2, 3, 4, 5, 101, 102, 103

Common Adverse Effects

Adverse effects reported in patients receiving conventional and sustained-release dextroamphetamine preparations include palpitations, tachycardia, blood pressure elevations, sudden death, myocardial infarction, reports of cardiomyopathy with chronic use, psychotic episodes (rare), overstimulation, restlessness, dizziness, insomnia, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, headache, motor and verbal tics, exacerbation of Tourette's syndrome, aggression, anger, logorrhea, dermatillomania, blurred vision, mydriasis, mouth dryness, unpleasant taste, diarrhea, constipation, intestinal ischemia, other gastrointestinal disturbances, anorexia, weight loss, urticaria, rash, angioedema, anaphylaxis, serious skin rashes (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), impotence, libido changes, frequent or prolonged erections, alopecia, and rhabdomyolysis.1, 2, 5, 101, 102

Common adverse effects reported in ≥5% of patients and at least twice the rate of placebo in pediatric patients ≥13 years of age receiving extended-release capsules containing mixed amphetamine salts (Mydayis^®) include decreased appetite, insomnia, nausea, irritability, and weight loss; in studies in adults, the most common adverse effects were insomnia, decreased appetite, dry mouth, weight loss, tachycardia, and anxiety.4

Common adverse effects reported in ≥5% of patients and with an incidence higher than placebo in pediatric patients 6-12 years of age receiving extended-release amphetamine capsules containing mixed amphetamine salts (Adderall XR^®) include loss of appetite, insomnia, abdominal pain, emotional lability, vomiting, nervousness, nausea, and fever.103 In pediatric patients 13-17 years of age, the most common adverse effects were loss of appetite, insomnia, abdominal pain, weight loss, and nervousness.103 In adults, the most common adverse effects were dry mouth, loss of appetite, insomnia, headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia, diarrhea, asthenia, and urinary tract infections.103

The most common adverse effects reported in patients receiving amphetamine extended-release oral suspension or extended-release oral tablets (Dyanavel^® XR) include dry mouth, anorexia, weight loss, abdominal pain, nausea, insomnia, restlessness, emotional lability, dizziness, and tachycardia.5

The most common adverse reactions reported in ≥2% of pediatric patients 6 to 17 years of age treated with dextroamphetamine transdermal system were decreased appetite, headache, insomnia, tic, abdominal pain, vomiting, nausea, irritability, increased blood pressure, and increased heart rate.3 The most common adverse reactions reported in ≥5% of adults treated with lisdexamfetamine (Vyvanse^®) in clinical studies (which were used to support efficacy of dextroamphetamine transdermal system) were decreased appetite, insomnia, dry mouth, diarrhea, nausea, and anxiety.3

Drug Interactions ⬆ ⬇

Amphetamines and amphetamine derivatives are metabolized to some extent by cytochrome P-450 (CYP) isoenzyme 2D6, and to a minor extent, inhibit CYP2D6 metabolism.103 In vitro, metabolites of amphetamine have also been shown to minimally inhibit CYP1A2 and CYP3A4.103 The effects of amphetamine or its metabolites in vivo on drug metabolism by CYP enzymes are not known.103 Amphetamine also inhibits monoamine oxidase (MAO).103

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 Inhibitors

Concomitant use of amphetamines with inhibitors of CYP2D6 may increase amphetamine exposure and the risk of serotonin syndrome.1, 2, 3, 4, 5, 101, 102, 103 Manufacturers suggest considering an alternative concomitant nonserotonergic medication or a medication that does not inhibit CYP2D6 in patients who are receiving CYP2D6 inhibitors.1, 2, 3, 101, 102, 103

Patients receiving concomitant CYP2D6 inhibitors should be initiated at lower amphetamine dosages and monitored for signs and symptoms of serotonin syndrome, especially when initiating dextroamphetamine and during dosage increases.1, 2, 3 If serotonin syndrome occurs, dextroamphetamine therapy and the CYP2D6 inhibitor should both be discontinued.1, 2, 3

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2 Substrates

The manufacturer states that based on pharmacokinetic data, no dosage adjustment of CYP1A2 substrates (e.g., theophylline, duloxetine, melatonin) is needed when dextroamphetamine transdermal system (Xelstrym^®) is used concomitantly.3

CYP2D6 Substrates

The manufacturer states that based on pharmacokinetic data, no dosage adjustment of CYP2D6 substrates (e.g., atomoxetine, desipramine, venlafaxine) is needed when dextroamphetamine transdermal system (Xelstrym^®) is used concomitantly.3

CYP3A4 Substrates

The manufacturer states that based on pharmacokinetic data, no dosage adjustment of CYP3A4 substrates (e.g., midazolam, pimozide, simvastatin) is needed when dextroamphetamine transdermal system (Xelstrym^®) is used concomitantly.3

CYP2C19 Substrates

The manufacturer states that based on pharmacokinetic data, no dosage adjustment of CYP2C19 substrates (e.g., omeprazole, lansoprazole, clobazam) is needed when dextroamphetamine transdermal system (Xelstrym^®) is used concomitantly.3

Acidifying Agents

Concomitant administration of agents that alter GI and urinary pH can impact urinary excretion and affect plasma levels of amphetamine.5 Concomitant use of acidifying agents (e.g., ascorbic acid) decrease plasma levels of amphetamine.5 Lower plasma levels of amphetamine may reduce efficacy; therefore, a dosage increase may be warranted based on clinical response.5

Concomitant administration of the urinary acidifying agent methenamine increases the urinary excretion of amphetamine, which reduces efficacy.1

Alkalinizing Agents

Concomitant administration of agents that increase GI and urinary pH (e.g., sodium bicarbonate) can increase plasma levels of amphetamine, potentiating its activity.5 Alkaline urine pHs result in less ionization and reduced renal elimination of amphetamine.4 Some manufacturers recommend avoiding concomitant use of GI and urinary alkalinizing agents,5, 103 while others recommend exerting caution and adjusting amphetamine dosage accordingly.4

Anticonvulsants

Intestinal absorption of ethosuximide, phenobarbital, or phenytoin may be delayed when used concomitantly with amphetamines.1 Synergistic anticonvulsant activity may also be observed with concomitant use of phenobarbital or phenytoin.1

Antihistamines

Concomitant use of amphetamines may counteract the sedative effects of antihistamines.1

Antihypertensive Agents

Concomitant use of amphetamines may antagonize the blood pressure-lowering effects of antihypertensive medications and inhibit the effects of adrenergic blockers.1

Chlorpromazine

Concomitant use of chlorpromazine blocks dopamine and norepinephrine receptors, inhibiting the central stimulatory effect of amphetamines.1 Chlorpromazine can be used for the treatment of amphetamine poisoning.1

Guanfacine

The manufacturer states that no dosage adjustments of guanfacine or dextroamphetamine transdermal system (Xelstrym^®) are needed when used concomitantly.3

Haloperidol

Haloperidol, which blocks dopamine receptors, inhibits the central stimulatory effect of amphetamine.1

Lithium

Concomitant use of lithium carbonate may block the anorectic and stimulatory effects of amphetamines.1

Meperidine

Concomitant use of meperidine with amphetamines may result in increased analgesia from meperidine.1

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs slow the metabolism of amphetamine and cause increased release of norepinephrine and other monoamines from adrenergic nerves; headaches and hypertensive crises can occur.3 Concomitant use of amphetamines is contraindicated in patients taking MAOIs or within 14 days of discontinuing an MAOI (including linezolid and IV methylene blue).3

Norepinephrine

Concomitant use of norepinephrine with amphetamines may increase adrenergic effects with norepinephrine.1

Proton Pump Inhibitors

Peak plasma concentrations of amphetamine are decreased when the medication is used concomitantly with proton pump inhibitors (e.g., omeprazole).101 When proton pump inhibitors are used concomitantly with amphetamines, monitor patients for changes in clinical efficacy and adjust therapy as needed based on clinical response.101

Serotonergic Drugs

Potentially fatal serotonin syndrome can occur when amphetamines are used in conjunction with other serotonergic medications that affect serotonergic neurotransmitters, such as MAOIs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants (TCAs), fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort ( Hypericum perforatum ).1, 2, 3, 4, 5, 101, 102, 103

Concomitant use of TCAs can cause significant increases in d-amphetamine in the brain and can potentiate the cardiovascular effects of amphetamines.3 If a TCA is used concomitantly, monitor patients frequently and adjust or use alternate medication therapy based on clinical response.3

Concomitant use of amphetamines with other serotonergic medications should be only used if potential benefits justify the potential risks.4 If clinically feasible, consider initiating amphetamine therapy at a reduced dosage.4 Monitor patients for the emergence of serotonin syndrome during therapy initiation or titration.1, 2, 3, 4, 5, 101, 102, 103

Veratrum Alkaloids

Amphetamines inhibit the blood pressure-lowering effects of veratrum alkaloids.1

Other Information ⬆ ⬇

Description

Dextroamphetamine sulfate is the dextrorotatory isomer of d,l-amphetamine sulfate, a non-catecholamine, sympathomimetic amine with CNS-stimulating activity.1 The pharmacologic action of amphetamines involved in the treatment of ADHD has not been fully elucidated; however, its actions are thought to be related to the blockade of norepinephrine and dopamine reuptake into presynaptic neurons and the increased release of norepinephrine and dopamine into the extraneuronal space.101 Other than CNS stimulant activity, peripheral actions of amphetamines include elevation of systolic and diastolic blood pressure, weak bronchodilation, and weak respiratory stimulation.1

Commercially available dextroamphetamine products include single-entity products and fixed combination products that contain mixed amphetamine salts.1, 2, 3, 4, 5, 101, 102, 103 Conventional (short-acting) formulations include dextroamphetamine sulfate tablets (Zenzedi^®), dextroamphetamine sulfate oral solution (Procentra^®), and conventional tablets containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Adderall^®).1, 2, 101 Sustained-release dextroamphetamine sulfate capsules (Dexedrine^® Spansules^®) are considered an intermediate-acting formulation.102 A long-acting transdermal system formulation of dextroamphetamine (Xelstrym^®) is also available.3 Two formulations of extended-release capsules containing mixed amphetamine salts are commercially available.4, 103 One formulation of extended-release capsules containing mixed amphetamine salts (Mydayis^®) contains 3 types of drug-releasing beads (1 type of immediate-release and 2 types of delayed-release beads),4 which allow for approximately one-third of the total to be delivered immediately, and the remaining two-thirds to be dissolved at pHs of 5.5 and 7.4, 554 The other formulation of extended-release capsules containing mixed amphetamine salts (Adderall^® XR) delivers the medicine in equal amounts as an immediate release dose and as a sustained-release second dose.554 Extended-release tablets and oral suspension (Dyanavel^® XR) containing amphetamine (complexed with sodium polystyrene sulfonate), amphetamine aspartate, and dextroamphetamine sulfate are also available.5

Following oral administration of conventional dextroamphetamine sulfate tablets, peak plasma concentrations were attained after approximately 3 hours.1 Following oral administration of conventional tablets containing mixed amphetamine salts (Adderall^®), peak plasma concentrations of d-amphetamine and l-amphetamine were attained at 3 hours.101 The pharmacokinetics of d-amphetamine and l-amphetamine are dose-proportional over the oral dosing range of 10<30 mg.101 Effects persist for 4<6 hours after oral administration of conventional preparations of dextroamphetamine sulfate and mixed amphetamine salts (Adderall^®).554 The effect of food on the pharmacokinetics of mixed amphetamine salts (Adderall^®) has not been evaluated.101

Following oral administration of sustained-release capsules containing dextroamphetamine sulfate (Dexedrine^® Spansules^®), peak plasma concentrations of dextroamphetamine occur after 8 hours.102

Following oral administration of extended-release capsules containing mixed amphetamine salts (Adderall^® XR), peak plasma concentrations are attained at 7 hours.103 The pharmacokinetics of Adderall XR^® are dose proportional over the oral dosing range of 20<60 mg in adults and adolescents that weigh >75 kg, over 10<40 mg in adolescents that weigh ≤75 kg, and over 5<30 mg in children 6<12 years of age.103 There is no expected accumulation of Adderall XR^® at steady state when used in children.103 Food does not affect the absorption of d- or l-amphetamine from Adderall XR^®, but administration with a high-fat meal prolongs the time to peak plasma concentrations for d-amphetamine from 5.2 hours to 7.7 hours, and for l-amphetamine from 5.6 hours to 8.3 hours.103 There is comparable absorption to the intact capsule in the fasting state when the contents are opened and sprinkled onto applesauce.103 A single 20 mg dose of extended-release capsules containing mixed amphetamine salts (Adderall XR^®) provides comparable plasma concentrations of d-amphetamine and l-amphetamine to immediate-release mixed amphetamine salts (Adderall^®) 10 mg twice daily administered 4 hours apart.103 The duration of action of Adderall XR^® is approximately 10-12 hours.554

Following oral administration of extended-release capsules containing mixed amphetamine salts (Mydayis^®) in adults and pediatric patients, peak plasma concentrations occurred at 8 hours for d- and l-amphetamine in adults, and at 7<10 hours in pediatric patients.4 The pharmacokinetics of Mydayis^® are linear and dose proportional over the oral dosing range of 12.5<50 mg; steady state is achieved after 7<8 days of standard dosing.4 Mydayis^® has a mean accumulation ratio of 1.6.4 A single 37.5 mg dose of Mydayis^® provides plasma exposure to d- and l-amphetamine comparable to that with a 25 mg dose of Adderall XR^® followed by a 12.5 mg dose of immediate-release amphetamine 8 hours later.4 Following oral administration of extended-release capsules of mixed amphetamine salts (Mydayis^®) in the fasting state, peak plasma concentrations of d-amphetamine are attained at 7 hours, and l-amphetamine at 7.5 hours.4 When administered with a high-fat meal, absorption is not affected, but peak plasma concentrations of d- and l-amphetamine are delayed to 12 hours.4 There is comparable absorption to the intact capsule in the fasting state when the contents are opened and sprinkled onto applesauce.4 The duration of action of Mydayis^® is estimated to be up to 16 hours.4 In vitro studies evaluating the effect of alcohol on the release of amphetamine indicate increased release of Mydayis^® in the presence of 20% alcohol concentration, and more noticeably, at a 40% alcohol concentration.4

Following oral administration of extended-release suspension (Dyanavel^® XR) in adults, the median time to peak plasma concentrations was 4 hours for d-amphetamine and l-amphetamine.5 After oral administration of extended-release tablets (Dyanavel^® XR) in adults, the median time to peak plasma concentrations was 5 hours for d-amphetamine and l-amphetamine.5 Under fasting conditions, chewing or swallowing the extended-release tablets does not significantly impact amphetamine exposure or time to peak plasma concentrations.5 In pediatric patients 6<12 years of age under fasting conditions, the median time to peak plasma concentrations following oral administration of extended-release suspension (Dyanavel^® XR) was 3.9 hours for d-amphetamine and 4.5 hours for l-amphetamine.5 The relative bioavailability of extended-release suspension (Dyanavel^® XR) is 106% for d-amphetamine and 111% for l-amphetamine compared with an equal dosage of Adderall^®, and is 94% for both d- and l-amphetamine compared to Adderall XR^®.5 The relative bioavailability of an equivalent dosage of extended-release tablets compared to extended-release suspension is 105% for d-amphetamine and 106% for l-amphetamine.5 Administration of the extended-release suspension with a high fat meal delays the time to peak plasma concentrations by 1 hour, increases maximum plasma concentrations by 2%, and decreases exposure to d- amphetamine by 5.7% and l-amphetamine by 7.4%.5 Following oral administration of the extended-release tablets with a high fat meal, maximum plasma concentrations are decreased by 3%; total exposure to d-amphetamine is decreased by 4%, and total exposure to l-amphetamine is decreased by 7.3%.5 The duration of action of Dyanavel^® XR extended-release suspension and tablets is approximately 13 hours.554 In vitro studies evaluating the effect of alcohol on the extended-release oral suspension showed that in the presence of 40% alcohol concentration, there was dose dumping potential.5 When extended-release oral tablets were evaluated, there was no alcohol-induced dumping in the presence of 40% alcohol.5 Dose dumping was also not observed in the presence of 5%, 10%, or 20% alcohol for the extended-release suspension or tablets.5

Following a single application of the dextroamphetamine transdermal system (Xelstrym^®), peak plasma concentrations occurred in 6-9 hours; peak plasma concentrations occurred in 6 hours following repeated application.3 Application of a heating pad shortens the median time to peak plasma concentrations by 2 hours and increases peak plasma concentrations and total exposure over 9 hours by 16% and 50%, respectively.3 Application of the transdermal system to various recommended sites (e.g., hip, upper arm, chest, upper back, or flank) does not alter dextroamphetamine pharmacokinetics.3

Although some of the enzymes involved in metabolism have not been fully elucidated, cytochrome P-450 (CYP) isoenzyme 2D6 is known to be involved in the oxidation of 4-hydroxyamphetamine.101 Because CYP2D6 is polymorphic, there is a potential for variability in metabolism amongst patients.101 Amphetamine reportedly undergoes oxidation to form several metabolites, which include 4-hydroxyamphetamine, alpha-hydroxy-amphetamine, and norephedrine.101 Norephedrine and 4-hydroxyamphetamine are active metabolites of amphetamine, which undergo subsequent oxidation to form 4-hydroxy-norephedrine.101 Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, and ultimately, benzoic acid and its glucuronide and glycine conjugate hippuric acid.101

The elimination half-life of dextroamphetamine sulfate oral solution (ProCentra^®) is 11.75 hours.2 The elimination half-life of conventional dextroamphetamine sulfate tablets (Zenzedi^®) and sustained-release dextroamphetamine sulfate capsules (Dexedrine^® Spansule^®) is approximately 12 hours.1, 102

Following removal of the dextroamphetamine transdermal system (Xelstrym^®) after 9 hours, the mean elimination half-life was approximately 6.4 hours in pediatric patients and 11.5 hours in adults.3

Following oral administration of conventional mixed amphetamine salts (Adderall^®), the mean elimination half-life ranges from 9.77<11 hours for d-amphetamine and from 11.5<13.8 hours for l-amphetamine.101

Following oral administration of extended-release dextroamphetamine sulfate in fixed combination with other amphetamines (Mydayis^®) in pediatric and adult patients, the mean elimination half-life of d-amphetamine ranges from 10<11 hours, and the mean elimination half-life of l-amphetamine ranges from 10<13 hours.4

The mean elimination half-life of extended-release mixed amphetamine salts (Adderall^® XR) is shorter for children than for adults.103 When adjusted for weight, amphetamine exposure is 30% less in children.103 The elimination half-life of d-amphetamine is 9 hours in children 6<12 years of age, 11 hours in adolescents 13<17 years of age, and 10 hours in adults.103 For the l-amphetamine isomer, the elimination half-life is 11 hours in children 6<12 years of age, 13<14 hours in adolescents, and 13 hours in adults.103

Following oral administration of extended-release amphetamine oral suspension (Dyanavel^® XR), the mean elimination half-life was 12.4 hours for d-amphetamine and 15.1 hours for l-amphetamine.5 Following oral administration of extended-release amphetamine tablets (Dyanavel^® XR), the mean elimination half-life was 13.5 hours for d-amphetamine and 17.3 hours for l-amphetamine.5 In pediatric patients 6<12 years of age, the mean elimination half-life of the extended-release oral suspension was 10.4 hours for d-amphetamine and 12.1 hours for l-amphetamine.5

Amphetamine has a pKa of 9.9; therefore, urinary recovery of amphetamine is highly dependent on urine pH and flow rates.101 At normal urinary pHs, approximately 50% of an amphetamine dose is recovered in urine as derivatives of alpha-hydroxy-amphetamine, and another 30<40% in urine as unchanged amphetamine. Acidic urinary pH and high flow rates result in increased renal elimination that exceeds the clearance of glomerular filtration rates, while alkaline urinary pHs result in reduced ionization and renal elimination.101 The urinary recovery of amphetamine ranges from 1<75%, which depends on urinary pH; the remainder of the dose undergoes hepatic metabolism.101 Both renal and hepatic impairment can inhibit the elimination of amphetamine and prolong exposure.101

Advice to Patients

Educate patients and their families on the risks of abuse, misuse, and addiction of amphetamines, which can lead to overdose and death, and inform them on proper disposal of unused medication.1, 2, 3, 4, 5, 101, 102, 103 Advise patients to store amphetamines in a safe, preferably locked place, and to not give their medication to anyone else.1, 2, 3, 4, 5, 101, 102, 103
Inform patients there are potential risks with amphetamine therapy in patients with serious heart disease, such as sudden death.1, 2, 3, 4, 5, 101, 102, 103 Patients or caregivers should inform clinicians immediately if adverse cardiovascular effects (e.g., exertional chest pain, unexplained syncope, other symptoms suggestive of cardiac disease) occur during stimulant therapy.1, 2, 3, 4, 5, 101, 102, 103
Inform patients that amphetamines can cause elevations in blood pressure and heart rate and they should be monitored for these effects.1, 2, 3, 4, 5, 101, 102, 103
Inform patients that amphetamines, even at recommended doses, can cause psychotic or manic symptoms even in patients without a prior history of psychotic symptoms or mania.1, 2, 3, 4, 5, 101, 102, 103
Inform patients and caregivers that growth should be monitored during amphetamine therapy in pediatric patients, and patients that are not growing or gaining weight as expected may require treatment interruption.1, 2, 3, 4, 5, 101, 102, 103
Inform patients about the risk of peripheral vascular disorders, including Raynaud's phenomenon, and the associated signs and symptoms (e.g., feelings of numbness, coolness, or pain in fingers or toes; changes in color from pale to blue to red).1, 2, 3, 4, 5, 101, 102, 103 Advise patients to report any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes to their clinician and to immediately contact their clinician if any signs of unexplained wounds appear on fingers or toes.1, 2, 3, 4, 5, 101, 102, 103 Rheumatology referral may be appropriate for certain patients.1, 2, 3, 4, 5, 101, 102, 103
Inform patients amphetamines can lower the seizure threshold.1, 2, 3, 4, 5, 101, 102, 103 Advise patients to contact their healthcare provider immediately and to discontinue amphetamine therapy if a seizure occurs.1, 2, 3, 4, 5, 101, 102, 103
Inform patients of the risk of serotonin syndrome with concomitant use of amphetamine and other drugs that affect serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), linezolid, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort ( Hypericum perforatum ).1, 2, 3, 4, 5, 101, 102, 103 Advise patients to contact their healthcare provider or report to the emergency department immediately if symptoms of serotonin syndrome occur.1, 2, 3, 4, 5, 101, 102, 103
Inform patients that motor and verbal tics and worsening of Tourette's syndrome can occur with amphetamine therapy.1, 2, 3, 4, 5, 101, 102, 103 Patients should notify their healthcare provider if there are new, emerging, or worsening of tics or Tourette's syndrome.1, 2, 3, 4, 5, 101, 102, 103
Advise patients to avoid alcohol while taking certain formulations of extended-release amphetamine since alcohol can cause rapid release of the drug.4, 5
Advise patients to avoid exposing the dextroamphetamine transdermal system to direct heat sources such as hair dryers, heating pads, electric blankets, and heated water beds while wearing it.3 Advise patients that in order to minimize skin irritation, discomfort, or pain with the patch, the application site should be changed each day.3
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses (e.g., cardiac/cardiovascular disease, thyroid disease, glaucoma, suicidal ideation or behaviors, mental/psychiatric disorder, seizures, hepatic or renal disease).1, 2, 3, 4, 5, 101, 102, 103
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1, 2, 3, 4, 5, 101, 102, 103 Inform patients that there is a pregnancy registry for females exposed to amphetamines during pregnancy.1, 2, 3, 4, 5, 101, 102, 103 Inform breastfeeding women that breastfeeding while taking amphetamines is not recommended.1, 2, 3, 4, 5, 101, 102, 103
Advise patients of other important precautionary information.1, 2, 3, 4, 5, 101, 102, 103

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dextroamphetamine and dextroamphetamine sulfate preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.